Selegiline modifies the extinction of responding following morphine self-administration, but does not alter cue-induced reinstatement, reacquisition of morphine reinforcement, or precipitated withdrawal.

Selegiline is an irreversible inhibitor of monoamine oxidase (MAO) with psychostimulant and neuroprotective effects which can prevent decreases in dopamine efflux that follow opiate withdrawal. The present study evaluated effects of selegiline treatment on morphine-seeking behavior and morphine reinforcement in Wistar rats (n = 26). In additional animals (n = 30), the ability of single doses of selegiline to modify naloxone-precipitated withdrawal was determined. After pretreatment with noncontingent morphine to establish opiate dependence, rats acquired self-administration of intravenous morphine. Daily intravenous treatment with saline or 2.0mg kg(-1) doses of selegiline was then initiated and continued over 14 days during extinction, reinstatement, and reacquisition of morphine self-administration. To reduce the potential for psychostimulant effects, selegiline was administered approximately 1h following self-administration, extinction, or reinstatement sessions. In some animals (n = 23), effects of saline or selegiline administration on locomotor activity were determined following extinction sessions. Daily selegiline treatment decreased the number of ratios completed and increased response latency during extinction, without modifying these measures during reinstatement or reacquisition of morphine self-administration. Chronic selegiline treatment increased locomotor activity recorded between 4 and 7h after selegiline administration on day 7 of extinction, but otherwise did not alter locomotor activity. Pretreatment with single, 2.0mg kg(-1) doses of selegiline did not modify naloxone-precipitated withdrawal. In conclusion, pretreatment with selegiline produced only a small decrease in responding during extinction of morphine self-administration and did not modify cue-induced reinstatement of morphine-seeking behavior, reacquisition or morphine reinforcement, or precipitated withdrawal.     

Modulation of the endogenous opioid system after morphine self-administration and during its extinction: a study in Lewis and Fischer 344 rats

Lewis (LEW) and Fischer 344 (F344) rats show differential morphine self-administration rates. In this study, after animals of both strains self-administered morphine (1mg/kg) or extinguished this behaviour for 3, 7 or 15days, we measured the binding to, and functional state of mu opioid receptors (MORs) as well as proenkephalin (PENK) mRNA content in several brain regions. The results showed that in most brain areas: 1) LEW rats had less binding to MORs in basal conditions than F344 rats; 2) after morphine self-administration, either one of the strains or both (depending on the brain area) showed increased levels of binding to MORs as compared to basal groups; and 3) these binding levels in morphine self-administration animals came down in each extinction group. Moreover, F344 rats exhibited, in general, an increased functionality of MORs after morphine self-administration, as compared to basal groups, which also went down during extinction. Finally, the basal content of PENK mRNA was lower in LEW rats than in F344 rats and it decreased more after self-administration; during extinction, the levels of PENK mRNA got normalized in this strain. This differential modulation of the endogenous opioid system might be related to the different rates of morphine self-administration behavior exhibited by both inbred rat strains.     

Differences in morphine reinforcement property in two inbred rat strains: associations with cortical receptors,behavioral activity,analgesia and the cataleptic effects of morphine

The purpose of the current study was to investigate genetic differences between two inbred strains of rats, Fisher-344 (F344/N) and Wistar Albino Glaxo (WAG/GSto), in a number of drug-naive and drug-related behaviors, including oral and intravenous morphine self-administration. F344/N and WAG/GSto rats differed in drug-naive behaviors such as nociception, rearing and sensitivity to lick suppression tests but did not differ in locomotor activity, ambulation or grooming behavior. F344/N rats were less sensitive to thermal stimuli as measured via tail-flick response, and more sensitive to the suppressive effects of intermittent shock in a lick suppression test. The F344/N rats demonstrated a significantly greater amount of rearing in open field tests but did not differ from WAG/GSto rats in locomotor activity, ambulation or grooming behavior. In addition to the behavioral results, naive F344/N and WAG/GSto rats were found to differ in and ₂ receptor concentrations (F344/N>WAG/GSto) and in 5HT₂ and D₂ affinity constants (WAG/GSto>F344/N). These two inbred rat strains also differed in drug-related behaviors. F344/N rats showed significantly greater depression of locomotor activity at morphine 3 mg/kg than WAG/GSto rats. In addition, F344/N rats consumed significantly greater amounts of morphine in a two-bottle choice procedure and morphine maintained significantly greater amounts of behavior during intravenous self-administration sessions. Importantly, drug maintained behavior was significantly greater than with vehicle only in the F344/N rats during operant self-administration sessions.     

Strain differences between Lewis and Fischer 344 rats in the modulation of dopaminergic receptors after morphine self-administration and during extinction

The Lewis (LEW) and Fischer 344 (F344) rat strains have been used as a model to study genetic vulnerability to drug addiction and they differ in their dopaminergic systems. We have studied the variation in the D1-like and D2-like receptors in distinct brain regions of LEW and F344 rats that self-administered morphine (1 mg/kg) for 15 days and also after different extinction periods (3, 7 and 15 days). Under basal conditions, binding to D1-like receptors in the olfactory tubercle and substantia nigra, and to D2-like receptors in the Pyriform cortex and hippocampal-CA1 was lower in LEW rats than in F344 rats. Conversely, the LEW rats exhibited stronger D2-like binding in the caudate-putamen. In most brain regions there was a decrease in D1-like binding in LEW rats after self-administration while the F344 animals displayed an increment. Additionally, D2 receptors of LEW rats were down-regulated after self-administration in the caudate-putamen and in the nucleus accumbens (shell and core divisions). Binding to D1-like receptors increased in both strains in the early phases of extinction, while in the later stages a differential regulation was observed between both strains. During the early phases of extinction only F344 rats showed alterations in D2-like receptor binding, however in the latter phases a specific modulation occurred in both strains. These differences in basal D1-like and D2-like receptor binding, and their differential modulation after self-administration and during extinction, may be reflected in the greater vulnerability to opiate addiction shown by LEW strain.     

Naloxone-precipitated conditioned taste aversions in morphine-dependent Fischer (F344) and Lewis rat strains

The Fischer 344 (F344) and Lewis (LEW) rat strains are genetically divergent populations that are used to study the effects of and responses to drugs of abuse. In this context, LEW rats display faster acquisition of drug self-administration than F344 rats. Interestingly, these strains have also been reported to differ in their somatic responses to morphine withdrawal. To address possible strain differences in the affective response to withdrawal, the present study assessed the ability of naloxone-precipitated withdrawal from morphine to induce conditioned taste aversions in male F344 and LEW rats. Specifically, subjects from each of these strains were given chronic morphine to induce dependence and then given access to a novel saccharin solution followed by naloxone. These pairings were given every fourth day for a total of two conditioning trials after which subjects were given access to saccharin but without naloxone administration to assess extinction of the naloxone-induced aversion. Behavioral assays of withdrawal were also performed after each naloxone administration. Both F344 and LEW subjects acquired aversions to the naloxone-associated taste with no significant differences in the rate of acquisition of the aversions. Differences did appear during extinction with LEW animals extinguishing the taste aversion significantly faster than F344 animals. The data were discussed in terms of the relative strength of the affective responses during withdrawal and the role of such responses to drug use and abuse.     

Black agouti (ACI) rats show greater drug- and cue-induced reinstatement of methamphetamine-seeking behavior than Fischer 344 and Lewis rats

Fischer 344 (F344) and Lewis (LEW) rats differ in methamphetamine self-administration (SA) and methamphetamine-induced reinstatement of previously extinguished behavior. We sought to determine whether genetic background also influences methamphetamine reinforcement efficacy, conditioned reinstatement, and methamphetamine-primed reinstatement of responding in F344, LEW, and Black Agouti (ACI) rats. We implanted rats with jugular catheters and trained them to self-administer methamphetamine (0.06 mg/kg/infusion) under a progressive ratio (PR) schedule of reinforcement during daily 2-h SA sessions. A compound stimulus (light+tone; LT) was paired with each infusion. Dose-dependent intake was determined for each rat. Rats then entered the extinction phase of the experiment where responding resulted in no programmed consequences. Following extinction sessions, rats underwent conditioned reinstatement testing. For conditioned reinstatement, rats received response-contingent presentations of the LT and no methamphetamine. Last, methamphetamine-primed reinstatement test sessions where conducted where subjects received experimenter delivered infusions of methamphetamine (0.06, 0.12, or 0.24 mg/kg). The strains did not differ in PR responding across the doses tested. The ACI rats demonstrated the highest behavioral output during extinction training, conditioned- and methamphetamine-primed reinstatement of previously extinguished behavior compared to the other strains. These data suggest that genetic background differentially influences extinction, conditioned reinstatement and methamphetamine-primed reinstatement in rats.     

Differences in extinction responding and reinstatement of methamphetamine-seeking behavior between Fischer 344 and Lewis rats

Fischer 344 (F344) and Lewis (LEW) rats differ in a number of self-administration behaviors. Whether or not these strains differ in methamphetamine-primed reinstatement of extinguished responding is unknown. F344 and LEW rats were trained to self-administer intravenous (i.v.) methamphetamine (0.06 mg/kg) during daily 2-h limited access sessions for 14 days. Following methamphetamine self-administration, subjects underwent a minimum of 6 extinction sessions where responding on the previously active lever resulted in no programmed consequences. Following extinction sessions, we evaluated strain and dose dependency of methamphetamine-primed (0.06, 0.12, or 0.24 mg/kg/i.v.) reinstatement of responding. All subjects received each dose once. Dosing order was determined by utilizing a within-subjects Latin square design. We found partial strain differences in daily methamphetamine self-administration. In addition, F344 rats responded significantly more during the first extinction session compared LEW rats. Last, the LEW rats demonstrated a heightened propensity to reinstate responding following methamphetamine priming injections compared to F344 rats. Our results suggest that genetic background influences differences in methamphetamine-seeking behaviors in rats.     

Effects of cocaine on locomotor activity and schedule-controlled behaviors of inbred rat strains

Effects of cocaine on several behaviors considered to be reflective of psychomotor stimulation were compared in F344/CR1BR and NBR/NIH inbred rat strains. Effects of cocaine on locomotor activity were compared with effects on either bar-press or nose-poke responses maintained under a multiple fixed-interval 3-min, timeout 1-min schedule of food presentation. In locomotor activity experiments, NBR rats were twice as active as F344 rats under baseline conditions and displayed dose-dependent increases in locomotion (5-20 mg/kg). Maximal increases in locomotor activity of F344 rats were only 200% compared to 1000% in NBR rats. In contrast to locomotor activity, no strain differences in the effects of cocaine were observed under the schedules of food delivery. Bar-pressing under the fixed-interval schedule was increased to a maximum of 150% of control in both rat strains. Nose-poke responding under the fixed-interval schedule was not significantly increased, but timeout rates were increased in both strains. These results suggest that NBR and F344 rats do not differ in general sensitivity to stimulant effects of cocaine but exhibit marked differences in responsivity to cocaine that are dependent upon the behavior studied. Further delineation of the behavioral specificity of strain differences in sensitivity to cocaine should help to identify neurobiological substrates underlying unique biologically determined responses to cocaine.     

Agmatine blocks acquisition and re-acquisition of intravenous morphine self-administration in rats

Our previous studies showed that agmatine inhibits morphine-induced conditioned place preference, locomotor sensitization and drug discrimination in rats. In the present study, we investigated the effects of agmatine on intravenous morphine self-administration in rats. At a dose of 80 mg/kg/infusion, agmatine did not substitute for intravenous morphine (0.5 mg/kg/infusion) self-administration, suggesting that agmatine itself has no reinforcing effect. However, pretreatment with agmatine (40 or 80 mg/kg, i.g.) significantly inhibited the acquisition of intravenous morphine self-administration as assessed by the nose-poke response and morphine intake. The mean number of days required to meet the acquisition criteria for intravenous morphine self-administration was significantly prolonged. After acquisition of intravenous morphine self-administration, chronic administration of agmatine (40 or 80 mg/kg × 30 days, bid, i.g.) during the extinction period significantly prevented the re-acquisition of intravenous morphine self-administration. The ability of agmatine to inhibit the acquisition and re-acquisition of intravenous morphine self-administration suggests a possible use of agmatine in the treatment of opioid dependence.     

Strain differences in response to escapable and inescapable novel environments and their ability to predict amphetamine-induced locomotor activity

Rationale. Locomotor response to novelty predicts locomotor and reinforcing effects of psychostimulant drugs in outbred rats. Among Lewis and Fischer 344 (F344) inbred rats this association is less clear, perhaps due to strain-selective differences in responses to novelty. Objective. We examined responses to novel inescapable and escapable environments and to novel objects in these strains. Methods. Experiment 1 utilized a place conditioning procedure. Rats were confined to one side for 8 days and then allowed access to both this (familiar) and the novel sides. Experiment 2 assessed locomotor response within an inescapable environment. On another occasion, contacts with novel objects within a novel environment were tabulated. Corticosterone levels and fecal boli were measured. Whether these responses predicted amphetamine-induced locomotor activity was determined. To further assess genetic contributions to this association, experiment 3 assessed novelty responses in F1 hybrid Lewis-F344 rats. Results. Lewis rats showed greater novelty-seeking behavior in the escapable environment but lower locomotor activity in the inescapable environment compared to F344 rats. There were no strain differences in novel object contacts, corticosterone, or fecal boli responses. Baseline corticosterone levels and activity levels in the novel environment were positively correlated with amphetamine activity based on data from all rats. However, novelty and amphetamine-induced activity showed non-significant negative correlations in F344 and Lewis rats. Yet, F1 rats showed a significant positive correlation between these variables, even though some of their other responses were Lewis-like or F344-like. Conclusions. These data suggest that responses to different novelty situations are strain-dependent. Electronic Publication     

Etonitazene delivered orally serves as a reinforcer for Lewis but not Fischer 344 rats.

Oral etonitazene self-administration was systematically investigated in two inbred strains of rats, Lewis (LEW) and Fischer 344 (F344). For LEW rats, etonitazene maintained higher rates of lever pressing and was consumed in larger volumes than the water vehicle when the reinforcement schedule was fixed ratio (FR) 8. In contrast, with F344 rats responding did not systematically exceed water values at any etonitazene concentration. LEW rats also drank substantially more etonitazene than F344 rats, and at FR 8 only LEW rats showed the typical inverted U-shaped function between etonitazene concentration and number of responses. For the LEW strain, response rate increased as FR size increased from FR 1 to FR 2 and FR 4, but decreased at FR 8. For the F344 strain, as FR size increased response rate showed small increases, but the response rates were far lower than those of the LEW strain. The results support the conclusion that etonitazene was an effective reinforcer for LEW but not F344 rats. These findings demonstrate genetic differences in opioid reinforcement of operant behavior and indicate that genotype can be an important determinant of whether etonitazene serves as a reinforcer.     

Different patterns of pharmacological reinstatement of cocaine-seeking behavior between Fischer 344 and Lewis rats

Rationale Fischer 344 (F344) and Lewis (LEW) rats differ in cocaine self-administration behaviors. Whether or not these inbred strains of rats differ in pharmacological reinstatement of cocaine-seeking behavior is unknown.Objectives The purpose of the present study was to determine if inbred strains of rats demonstrate differences in alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) and cocaine-induced reinstatement of previously extinguished cocaine-seeking behavior.Methods F344 and LEW rats received indwelling jugular catheters, bilateral guide cannula aimed at the nucleus accumbens core, and were trained to lever press for 0.5 mg/kg intravenous cocaine during 2-h self-administration sessions. Following 14 sessions, rats underwent extinction sessions, where previously reinforced lever pressing resulted in no programmed consequences. Just prior to beginning extinction session 7, rats received an intracranial infusion of saline. Lever pressing was not reinforced. During subsequent extinction sessions, rats received AMPA injections (0.2, 0.4, or 0.6 nM). Dosing order was determined by a within-subject Latin square design. At least two extinction sessions separated each AMPA session. Rats then underwent cocaine-induced reinstatement test sessions (lever pressing was not reinforced). Rats received passive intravenous cocaine (0.0, 0.5, 1.0, or 2.0 mg/kg) after being placed in the experimental chamber. At least two extinction sessions separated each cocaine-prime session, and subjects were tested at each dose according to a within-subjects Latin square design.Results LEW rats demonstrated blunted maximal responding to AMPA-induced reinstatement and heightened sensitivity to cocaine-induced reinstatement compared with F344 rats.Conclusions This study demonstrates that inbred strains differ in pharmacological reinstatement of cocaine-seeking behavior.     

Effects of d-amphetamine, WIN 35,428, pentobarbital and morphine on schedule-controlled responding in two inbred rat strains that differ in locomotor stimulatory effects of cocaine

Behavioral effects of d-amphetamine, the cocaine analog, WIN 35,428, morphine, and pentobarbital were compared in NBR/NIH and F344CR1BR rats. Either nose-poke or lever-press responding was maintained under 3-min fixed-interval schedules of food presentation. The effects of morphine, WIN 35,428 and pentobarbital depended upon the rat strain studied: morphine increased nose-poke responding in NBR but not F344 rats; significant strain x dose interactions were observed with WIN 35,428; and pentobarbital was more potent in decreasing nose-poke responding in NBR than in F344 rats. No strain differences were observed in the behavioral effects of d-amphetamine. There were also prominent differences in the effects of drugs that were related to the nature of the response requirement. In both rat strains, nose-poke responding was affected differently than lever-press responding by morphine, d-amphetamine, and WIN 35,428. Pentobarbital produced effects that were independent of the specified response topography. A global underlying difference in these rat strains cannot be identified at present to account for the diversity of findings. The behavioral effects of these drugs appear to be influenced by a host of interactive factors including the drug, strain of animal, the baseline response rate and physical dimensions of the response.     

Reinstatement of heroin-reinforced behavior following long-term extinction: implications for the treatment of relapse to drug taking

The effect of non-contingent priming injections of heroin on drug-reinforced behavior following long-term extinction was examined. Male rats were trained to lever press for 100μg/kg/infusion of intravenous heroin during four 6h sessions per day. The drug-reinforced behavior was extinguished by daily reductions in dose followed by at least 12 sessions of saline self-administration. A single non-contingent priming injection of heroin (100μg/kg, i.v.) resulted in the reinstatement of the drug-reinforced behavior, even though extinction conditions remained. The results indicate that the drug-induced reinstatement of previously extinguished drug-reinforced behavior is possible even after long periods of extinction. The implications of the present findings for the treatment of relapse to drug abuse in humans are discussed.     

Genetic differences in preferences for morphine and codeine in Lewis and Fischer 344 inbred rat strains

Preferences for morphine and codeine in two inbred strains of rats, Lewis and Fischer 344 (F344), were systematically investigated using the drug-admixed food (DAF) procedure. Rats were allowed access to food only between 10:00 a.m.-4:00 p.m., but allowed free access to water. The rats were allowed to choose either DAF (0.5 mg/g) or normal food on the first day and then were allowed access only to DAF on the second and third days. After this schedule was repeated 10 times, they were again allowed to choose either DAF or normal food for a successive 8 days. In both strains, preferences for morphine and codeine rapidly increased; the preferences in Lewis rats were significantly higher than those in F344 rats during the daily choice trials. In the range of 0.25 to 1 mg/g for the DAF concentration, there was a negative correlation between the preference and concentration in Lewis and F344 rats, except in the codeine group of F344 rats. When a test dose (60 mg/kg and 30 mg/kg, s.c., in Lewis and F344 rats, respectively) of morphine or codeine was given at 30 min before the beginning of the choice trial, Lewis rats, but not F344 rats, showed a significantly lower preference for the respective drug. The above results indicate that genotype is an important determinant of the degree of preferences for morphine and codeine.     

Inbred rat strain comparisons indicate different sites of action for cocaine and amphetamine locomotor stimulant effects

Cocaine and amphetamine produce several behavioral effects, most notably locomotor stimulation. Biochemically, evidence suggests specific involvement of dopaminergic systems, although not necessarily identical sites, in mediating cocaine- and amphetamine-induced locomotor stimulation. This study examined the effects of cocaine or amphetamine on locomotor activity in rats from the ACI, F344, LEW and NBR inbred strains. Dose-dependent increases in locomotor activity were found for both drugs in all strains. However, large potency and efficacy differences were found. Further, significant strain by drug interactions were found, in that the strain rank order for stimulant response to the two drugs was not identical. Since striatal dopaminergic neurons influence locomotor activity, we also assessed ligand affinity and receptor density of dopamine transporters and dopaminergic D₁ and D₂ receptors in striatal tissue from these same strains of rats. No differences in these receptor binding parameters were found. These findings support the conclusion that these two drugs produce their locomotor stimulant effects through different sites of action, and that genetic differences in response to these drugs at the behavioral level do not appear to be mediated significantly by differences in structure or number of striatal dopaminergic sites. The further use of genetic methods, however, may aid in determining the specific sites of action of these widely used stimulant drugs.     

Preexposure to MDMA ("Ecstasy") delays acquisition but facilitates MDMA-induced reinstatement of amphetamine self-administration behavior in rats

The current experiment investigated the effect of 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') preexposure on the acquisition of intravenous amphetamine self-administration and the reinstatement of amphetamine-seeking behavior by either MDMA or amphetamine. Rats were preexposed to a 5-HT depleting regime of MDMA (5 mg/kg every hour for 4 h on two consecutive days) or equivalent vehicle injections. Intravenous self-administration of low dose d-amphetamine (0.03 mg/kg/infusion) on a FR1 schedule was subsequently assessed. The rats were then given 2 weeks of extinction and tested for drug-seeking behavior with priming doses of amphetamine or MDMA. Brains were analysed for monoamine content using high-performance liquid chromatography (HPLC). MDMA-preexposed rats were initially slower to acquire amphetamine self-administration. However, by day 6 of acquisition, there was no difference from controls. Following extinction, amphetamine (1 mg/kg, i.p.) reinstated drug seeking and produced locomotor hyperactivity in both MDMA- and vehicle-pretreated animals. However, MDMA (5 mg/kg, i.p.) was only effective in producing amphetamine seeking and hyperactivity in MDMA-pretreated rats. MDMA pretreatment caused significant decreases in 5-hydroxy-indolacetic acid (5-HIAA) and 5-HT in several brain regions. These results suggest that 5-HT depletion induced by MDMA may initially slow the acquisition of amphetamine self-administration but that MDMA preexposure may also sensitize animals to the locomotor stimulating and priming effects of MDMA on drug-seeking behavior.     

D-cycloserine Deters Reacquisition of Cocaine Self-Administration by Augmenting Extinction Learning

Augmentation of cue exposure (extinction) therapy with cognitive-enhancing pharmacotherapy may offer an effective strategy to combat cocaine relapse. To investigate this possibility at the preclinical level, rats and squirrel monkeys were trained to self-administer cocaine paired with a brief visual cue. Lever pressing was subsequently extinguished by withholding cocaine injections while maintaining response-contingent presentations of the cue. The glycine partial agonist D-cycloserine (DCS; 15 and 30 mg/kg in rats, 3 and 10 mg/kg in monkeys) was evaluated for its effects on the rate of extinction and subsequent reacquisition of cocaine self-administration. Compared with vehicle, pretreatment with 30 mg/kg DCS 0.5 h before extinction training reduced the number of responses and latency to reach the extinction criterion in rats, but neither dose of DCS altered these measures in monkeys. In both species, pretreatment with the higher dose of DCS before extinction training significantly attenuated reacquisition of cocaine self-administration compared with either extinction training in the absence of DCS or DCS in the absence of explicit extinction. Furthermore, treatment with 30 mg/kg DCS accompanied by brief handling (a stress induction) immediately after but not 6 h after extinction training attenuated reacquisition of cocaine self-administration in rats. No adverse effects of 10 mg/kg DCS were evident in quantitative observational studies in monkeys. The results suggest that DCS augmented consolidation of extinction learning to deter reacquisition of cocaine self-administration in rats and monkeys. The results suggest that DCS combined with exposure therapy may constitute a rational strategy for the clinical management of cocaine relapse.     

Differences in morphine and cocaine reinforcement under fixed and progressive ratio schedules; effects of extinction, reacquisition and schedule design

Opiate reinforcement was evaluated under a progressive ratio (PR) schedule often used for psychostimulant self-administration (termed 'PR 3-4' because the third response requirement was four lever presses) and three additional schedules that were modified to provide successively lower levels of difficulty by decreasing the steepness of response requirement progression (termed 'PR 9-4', 'PR 14-4', and 'PR 26-4' because a response requirement of four was reached with step numbers of 9, 14 and 26, respectively). With the exception of the PR 3-4 schedule, all of the schedules supported morphine self-administration, and morphine self-administration during initial exposure and reacquisition did not differ by more than 10%. In contrast to morphine, cocaine was self-administered under the PR 3-4 schedule, with responding clearly exceeding levels during extinction. The PR 9-4 schedule was most suitable for morphine self-administration because it provided an intermediate level of difficulty, which supported levels of self-administration that exceeded values obtained under extinction but were less than those observed under FR-1. Under the PR 9-4 schedule, the number of self-administered injections of morphine was 61.5% of the number of injections obtained under a simple FR-1 schedule. This compares with a value of 21.0% for cocaine self-administration under the PR 3-4 schedule compared to an FR-1 schedule. These results show important differences in self-administration behavior supported by morphine and cocaine, which are consistent with a lower reinforcing efficacy for opiates relative to psychostimulants.     

Prevalence,magnitude, and correlates of an extinction burst in drug-seeking behavior in rats trained to self-administer nicotine during unlimited access (23 h/day) sessions

Rationale Animals trained to self-administer a variety of addictive drugs exhibit a temporary increase in response rate when saline is substituted for the drug (i.e., an “extinction burst”). However, the presence of an extinction burst in animal models of nicotine self-administration (NSA) has not been studied extensively. Objective The objective of the study was to examine the prevalence, magnitude, and correlates of an extinction burst in nicotine-seeking behavior using data from a previously published study and recently trained animals. Materials and methods Rats were trained to self-administer nicotine (0.03 mg/kg per infusion) during daily 23-h sessions. Saline extinction was subsequently arranged, followed by reacquisition of NSA for some animals. Results There was no increase in the daily infusion rate on the first day of extinction. However, a significant increase (35%) in mean peak 2-h infusion rates was observed within the first extinction session, indicative of an extinction burst. Greater extinction burst magnitude was correlated with higher infusion rates during the first 2 h of baseline sessions and smaller decreases in infusion rate at the end of extinction. In addition, animals with the slowest initial rates of extinction exhibited the fastest rates of reacquisition when unlimited access to nicotine was restored. Conclusions A modest increase in drug-seeking behavior occurred early within the first extinction session in rats trained to self-administer nicotine in unlimited access sessions. The presence of an extinction burst in nicotine-seeking behavior suggests similar mechanisms underlying extinction of NSA and self-administration of other drugs of abuse in animals and also parallels a similar phenomenon sometimes observed in smokers.